Hypophosphatemia promotes lower rates of muscle ATP synthesis.

Hypophosphatemia can lead to muscle weakness and respiratory and heart failure, but the mechanism is unknown. To address this question, we noninvasively assessed rates of muscle ATP synthesis in hypophosphatemic mice by using in vivo saturation transfer [31P]-magnetic resonance spectroscopy. By using this approach, we found that basal and insulin-stimulated rates of muscle ATP synthetic flux (VATP) and plasma inorganic phosphate (Pi) were reduced by 50% in mice with diet-induced hypophosphatemia as well as in sodium-dependent Pi transporter solute carrier family 34, member 1 (NaPi2a)-knockout (NaPi2a-/-) mice compared with their wild-type littermate controls. Rates of VATP normalized in both hypophosphatemic groups after restoring plasma Pi concentrations. Furthermore, VATP was directly related to cellular and mitochondrial Pi uptake in L6 and RC13 rodent myocytes and isolated muscle mitochondria. Similar findings were observed in a patient with chronic hypophosphatemia as a result of a mutation in SLC34A3 who had a 50% reduction in both serum Pi content and muscle VATP After oral Pi repletion and normalization of serum Pi levels, muscle VATP completely normalized in the patient. Taken together, these data support the hypothesis that decreased muscle ATP synthesis, in part, may be caused by low blood Pi concentrations, which may explain some aspects of muscle weakness observed in patients with hypophosphatemia.-Pesta, D. H., Tsirigotis, D. N., Befroy, D. E., Caballero, D., Jurczak, M. J., Rahimi, Y., Cline, G. W., Dufour, S., Birkenfeld, A. L., Rothman, D. L., Carpenter, T. O., Insogna, K., Petersen, K. F., Bergwitz, C., Shulman, G. I. Hypophosphatemia promotes lower rates of muscle ATP synthesis.

Direct innominate artery cannulation for selective antegrade cerebral perfusion during deep hypothermic circulatory arrest in aortic surgery.

OBJECTIVE: To demonstrate a novel, reproducible, and effective method of direct innominate artery cannulation using a 14 F pediatric venous cannula to establish antegrade cerebral protection (ACP) in patients undergoing aortic surgery that requires an open distal anastomosis or hemiarch replacement. METHODS: We reviewed prospectively gathered data on all patients who had undergone replacement of the ascending aorta or hemiarch with an open distal anastomosis using deep hypothermic circulatory arrest and direct innominate artery cannulation with a 14 F pediatric venous cannula at our institution. After central cannulation and cooling to 25 °C to 28 °C, all patients had ACP initiated by way of a direct innominate cannula placed over a guidewire. RESULTS: Fifty patients underwent direct innominate artery cannulation with our technique from 2010 to 2012. The operative mortality was 2% (n = 1), and the rates of neurologic morbidity were acceptable and similar to those with other methods of ACP delivery: stroke (2%, n = 1), seizure (0%, n = 0), and delirium (18%, n = 9). The mean operative time was 31 ± 9, 19 ± 5, 100 ± 39, 141 ± 39, and 259 ± 63 minutes for cooling, circulatory arrest, crossclamp, cardiopulmonary bypass, and total operative time, respectively. No local or arterial complications were observed. CONCLUSIONS: Direct cannulation of the innominate artery using a 14 F pediatric venous cannula is a simple, reproducible, safe, and effective technique for establishing ACP in patients undergoing aortic surgery that requires an open distal anastomosis or hemiarch replacement. This technique avoids the additional time and potential local complications associated with other established methods for delivering ACP, such as axillary cannulation.

Simulation and skills training in mitral valve surgery.

OBJECTIVE: Limited exposure and visualization and technical complexity have affected resident training in mitral valve surgery. We propose simulation-based learning to improve skill acquisition in mitral valve surgery. METHODS: After reviewing instructional video recordings of mitral annuloplasty in porcine and plastic models, 11 residents (6 integrated and 5 traditional) performed porcine model mitral annuloplasty. Video-recorded performance was reviewed by attending surgeon providing audio formative feedback superimposed on video recordings; recordings were returned to residents for review. After 3-week practice with plastic model, residents repeated porcine model mitral annuloplasty. Performance assessments initially (prefeedback) and at 3 weeks (postfeedback) were based on review of video recordings on 5-point rating scale (5, good; 3, average; 1, poor) of 11 components. Ratings were averaged for composite score. RESULTS: Time to completion improved from mean 31 ± 9 minutes to 25 ± 6 minutes after 3-week practice (P = .03). At 3 weeks, improvement in technical components was achieved by all residents, with prefeedback scores varying from 2.4 ± 0.6 for needle angles to 3.0 ± 0.5 for depth of bites and postfeedback scores of 3.1 ± 0.8 for tissue handling to 3.6 ± 0.8 for suture management and tension (P ≤ .001). Interrater reliability was greater than 0.8. In this sample, composite scores of first-year integrated and traditional residents were lower than those of senior level residents; comparatively, third-year integrated residents demonstrated good technical proficiency. CONCLUSIONS: Simulation-based learning with formative feedback results in overall improved performance of simulated mitral annuloplasty. In complex surgical procedures, simulation may provide necessary early graduated training and practice. Importantly, a "passing" grade can be established for proficiency-based advancement.

Muscle-specific IRS-1 Ser->Ala transgenic mice are protected from fat-induced insulin resistance in skeletal muscle.

OBJECTIVE: Insulin resistance in skeletal muscle plays a critical role in the pathogenesis of type 2 diabetes, yet the cellular mechanisms responsible for insulin resistance are poorly understood. In this study, we examine the role of serine phosphorylation of insulin receptor substrate (IRS)-1 in mediating fat-induced insulin resistance in skeletal muscle in vivo. RESEARCH DESIGN AND METHODS: To directly assess the role of serine phosphorylation in mediating fat-induced insulin resistance in skeletal muscle, we generated muscle-specific IRS-1 Ser(302), Ser(307), and Ser(612) mutated to alanine (Tg IRS-1 Ser-->Ala) and IRS-1 wild-type (Tg IRS-1 WT) transgenic mice and examined insulin signaling and insulin action in skeletal muscle in vivo. RESULTS: Tg IRS-1 Ser-->Ala mice were protected from fat-induced insulin resistance, as reflected by lower plasma glucose concentrations during a glucose tolerance test and increased insulin-stimulated muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. In contrast, Tg IRS-1 WT mice exhibited no improvement in glucose tolerance after high-fat feeding. Furthermore, Tg IRS-1 Ser-->Ala mice displayed a significant increase in insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activity and Akt phosphorylation in skeletal muscle in vivo compared with WT control littermates. CONCLUSIONS: These data demonstrate that serine phosphorylation of IRS-1 plays an important role in mediating fat-induced insulin resistance in skeletal muscle in vivo.